advanced modules for hbv · hepatitis b vaccine contains a viral protein: ‘hbsag= hepatitis b...

1 |World Health Organization

Western Pacific Region

Advanced modules for HBVAdvanced modules for HBV



HBV Module 1Hepatitis B serological markers

and virology

HBV Module 1Hepatitis B serological markers

and virology



HAV HBV HCV HDV HEVAcute hepatitis

Case fatality increases with age

Case fatality increases with age

Uncommon Superinfection in HBV may lead to fulminant disease

Higher case fatality in pregnant women

Chronic infection

No 5% (adults)90% (children)

55‐85%Complicates hepatitis B

Very rare

HCC* No Yes Yes NoRoute of transmission

WaterborneFoodbornePerson‐to person

PerinatalBloodborneSexual

BloodbornePerinatalSexual

Bloodborne WaterborneFoodborne

Vaccine Yes Yes No HBV vaccine NoTreatment options

None Available Available Modified treatment of

HBV

None

Main hepatitis virusesMain hepatitis viruses

*HCC; hepatocellular carcinoma



TECHNICAL CONSIDERATIONS AND CASE DEFINITIONS TO IMPROVE SURVEILLANCE FOR VIRAL HEPATITIS. (WHO 2016) P9

HBV HCVPersons who injected drugs ● ●

Sex workers ● ●

Men who have sex with men ● ●

Health‐care workers ● ●

Persons in long‐term care facilities ●

Persons on chronic dialysis treatment ● ●

Prisoners and other persons in closed setting ● ●

Persons who frequently receive blood/blood products ● ●

Children born to mother infected with HBV / HCV ● ●

Populations at higher risk for hepatitis B and CPopulations at higher risk for hepatitis B and C


Western Pacific RegionWHO guideline 2015

Who is at risk for chronic HBV infection ?Who is at risk for chronic HBV infection ? Age is a key factor in determining the risk of chronic

hepatitis B infection

80‐90% of infants infected during the first year of life

30‐50% of children infected before the age of 6 years

Less than 5% of otherwise healthy persons who are

infected as adults

20‐30% of adults who are chronically infected will

develop cirrhosis and/or liver cancer.



Who is at risk for chronic HBV infection ?Who is at risk for chronic HBV infection ?

WHO guideline 2015



Who to test for chronic HBV and HCV infectionWho to test for chronic HBV and HCV infection There are several possible approaches to testing for HBV

and HCV infection

General population testing

Focused or targeted testing of specific high‐risk groups

Routine antenatal clinic (ANC) testing

“Birth cohort” testing

Blood donor screening

GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P38‐39



Who to test for chronic HBV infectionWho to test for chronic HBV infectionTesting approach and population Recommendations

General population testing

In settings with a ≥2% or ≥5% HBsAg seroprevalence,all adults have routine access to and be offered HBsAg serological testing

Routine testing in pregnant women

In settings with a ≥2% or ≥5% HBsAg seroprevalence, HBsAgserological testing be routinely offered to all pregnant women in antenatal clinics

Focused testing in most affected populations

In all settings, HBsAg serological testing be offered to the following individuals• Adults and adolescents from populations most affected by

HBV infection• Adults, adolescents and children with a clinical suspicion of

chronic viral hepatitis• Sexual partners, children and other family members, and

close household contacts of those with HBV infection• Health‐care workers

Blood donors In all settings, screening of blood donors should be mandatory

GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P36



Initial assessment for chronic hepatitis B and CInitial assessment for chronic hepatitis B and C

HBV HCVChronic infection HBsAg Anti‐HCVAcute infection Anti‐HBc IgM HCV RNA, HCcAg etc.

(without anti‐HCV antibody, excluding other hepatitis viruses)



Additional assessment for chronic hepatitisAdditional assessment for chronic hepatitis

HBV HCVSerological markers

Anti‐HBs/anti‐HBc antibodiesHBe antigen, Anti‐HBe,

HBV DNA

HCV RNAHCV genotype

Severity Aminotransferase (AST/ALT)Bilirubin, albumin, alkaline phosphatase (ALP)

Staging Liver biopsyNon‐invasive tests

‐APRI, FIB‐4, FibroTest, Transietn elastography



Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection




How to test for chronic HBV infectionHow to test for chronic HBV infection(A) Single assay

(HBs seroprevalence ≥0.4%)

(B) Two assays(HBs seroprevalence <0.4%)




HBV Module 2Hepatitis B transmission and

prevention

HBV Module 2Hepatitis B transmission and

prevention



Transmission routes of HBVTransmission routes of HBV Vertical: Mother to child

Horizontal: Young children, household contacts

Sexual

Health‐care associated

Blood products

Unsafe injections

Medical procedure (i.e. Needle stick injury)

Persons who inject drugs (PWID)

Organs and tissue transplantation



HBV infection and age at acquisitionHBV infection and age at acquisition

Infections during infancy and early childhood are particularly likely to lead to chronic infection, with risk of cirrhosis and death (a public health problem)



Prevention of HBV infectionPrevention of HBV infectionVaccination*

Childhood vaccination• Primary 3-dose vaccination• Timely birth dose

High risk groups Catch‐up programs

Other measures Screening of blood and blood products Injection safety Occupational safety Harm reduction interventions Safe sex

* Is the key intervention to prevent chronic HBV infection(occurs following infection during infancy and childhood)



Infant and neonatal hepatitis B vaccinationInfant and neonatal hepatitis B vaccination Vaccination is the mainstay of Hepatitis B prevention

Infant and neonatal hepatitis B vaccination

The hepatitis B vaccination is the mainstay of

hepatitis B prevention

WHO recommends birth dose (BD) and 3rd dose

(B3) of hepatitis B vaccination

The complete vaccine series induces protective

antibody levels in >95% of infants and children.



Hepatitis B vaccineHepatitis B vaccine

Contains a viral protein: ‘HBsAg = Hepatitis B surface antigen’

Originally produced from plasma of persons with chronic HBV infection, but now only recombinant protein is used

Recombinant vaccine Gene for HBsAg is inserted into yeast or mammalian cells The cells are cultured to produce an excess of protein The protein is purified and adsorbed on the surface of an adjuvant

(alum) Used as intramuscular injection



Stability and storage Stability and storage

Hepatitis B vaccines

Storage at 2‐8°C

Relatively heat stable – remains effective even after several days at room temperature

However, very sensitive to freezing

Avoid freezing at all costs



Dose Protection

1 16%‐40%2 80%‐95%3 98%‐100%

Protection* in Infants by HBV Vaccination DoseProtection* in Infants by HBV Vaccination Dose

* Protection defined as anti‐HBs antibody titer of 10 mIU/mL or higherNote: Preterm infants less than 2 kg respond to vaccination less often



Hepatitis B vaccine response ratesHepatitis B vaccine response rates

A 3‐dose series induces protective antibody concentrations in >95% of healthy infants, children and young adults (<40 years)

Lower response rates in older adults (>40 years), obesity, smoking, chronic systemic illnesses

Seroprotection rates following vaccination in older persons

40‐49 years >90%

50‐59 years >80%



Vaccine non‐respondersVaccine non‐responders 5‐10% people may not respond to 3‐dose schedule

Most of the non‐responders do respond to an additional 3‐dose vaccination series

Alternative options for non‐responders

Double dose

Four dose schedule

Intradermal administration

Newer vaccines



Global health sector strategy on hepatitisGlobal health sector strategy on hepatitisTargets Interventions 2020 target 2030 target

1. Service coverage

1. Hep B3 vaccine 90% 90%

2. HBV PMTCT 50% 90%

3. Blood and injection safety95 % screened donations 100 % screened donations

50% RUP devices 90% RUP devices

4. Harm reduction 200 injection sets / PWID 300 injection sets / PWID

5. Treatment30% diagnosed 90% diagnosed

5M and 3M treated for HBV and HCV 80% eligible treated

2. ImpactA. Incidence ‐30%

(1% HBsAg in children )‐90%

(0.1% HBsAg in children)

B. Mortality ‐10% ‐65%

PMTCT: Prevention of mother to child transmissionPWID: Person who injects drugs



0

10

20

30

40

50

60

70

80

90

100

1990 1995 2000 2005 2010 2015

Coverage (%

)

Year

AfricanAmericanEastern MediterraneanEuropeanSouth East AsiaWestern PacificGlobal

Source: WHO AND UNICEF Joint Reporting

Immunization coverage with 3‐dose schedule of hepatitis B vaccine in infants in 2015

Immunization coverage with 3‐dose schedule of hepatitis B vaccine in infants in 2015



0

10

20

30

40

50

60

70

80

90

2000 2005 2010 2015

Coverage (%

)

Year

African

American

Western Pacific

Global

Source: WHO AND UNICEF Joint Reporting

Immunization CoverageImmunization Coverage


Western Pacific RegionEric Wiesen et al,Vaccine 2016WPRO

Regional vaccination coverageRegional vaccination coverage

Hepatitis B vaccine 3rd doseHepatitis B vaccine birth dose

Chronic infections



Catch‐up hepatitis B vaccination strategiesCatch‐up hepatitis B vaccination strategies All children and adolescents younger than 18 years‐

old and not previously vaccinated should receive the

vaccine if they live in countries where there is low or

intermediate endemicity.

Higher dose of vaccination might improve the lower

response in persons with HIV or with a low CD4 count.

Safer sex practices also protect against transmission

including minimizing the number of partners and

using barrier protective measures.



HBV Module 3Natural history of Hepatitis B

HBV Module 3Natural history of Hepatitis B



Consequences of HBV infectionConsequences of HBV infectionHepatitis B virus infection

Acute infection(short duration: <6 mo)

Chronic infection(duration >6 mo)

Asymptomatic

Acute viral hepatitis

Acute liver failure

Chronic hepatitis B

Cirrhosis: compensated

Cirrhosis: decompensated



Fulminant hepatitis

Rare, but to take care

40‐100%Death

*: IgM anti‐HBc(+) can distinguish acute infection from chronic infection

3‐5% (10% in Gt. A) in adults70‐95% in children

next slide

Acute HBV infectionHBsAg (+)

IgM anti‐HBc (+)HBV DNA(+), HBeAg(+/‐), Anti‐HBs(‐)

95% in adults5‐30% in children

Infection persistentHBsAg (+), Anti‐HBs (‐)

IgM anti‐HBc(‐), Anti‐HBc(+)HBV‐DNA(+), HBeAg(+/‐)

Infection resolvedHBsAg (‐), Anti‐HBs (+)

IgM anti‐HBc(‐), Anti‐HBc (+), HBV DNA(‐), HBeAg(‐)

*: Anti‐HBs (+) can distinguish resolved state from chronic infection

Natural history of HBV infection (Acute phase)Natural history of HBV infection (Acute phase)



Serological pattern of acute HBV infectionSerological pattern of acute HBV infection




Infection persistent

HBe(+) chronic hepatitis HBsAg (+), Anti‐HBc (+)

HBeAg (+), HBV DNA highALT high

HBe(‐) chronic hepatitis HBsAg (+), Anti‐HBc (+)

HBeAg (‐), HBV DNA low(‐high)ALT normal‐high

Inactive carrierHBsAg (+), Anti‐HBc (+)

HBeAg (‐), HBV DNA (‐)‐lowALT normal

Liver cirrhosis

Liver failureLiver cancer

Death

Clinical clearanceHBsAg (‐), Anti‐HBs (‐)

Anti‐HBc (+), HBV DNA (‐)ALT normal

Natural history of HBV infection (chronic phase)Natural history of HBV infection (chronic phase)



Natural history of chronic hepatitis BNatural history of chronic hepatitis B

Chronic hepatitis B

Immune‐tolerant phase

Immune‐active phase

Immune‐control phase

Reactivation phase

Immune clearance (cure)



Natural history of chronic hepatitis BNatural history of chronic hepatitis B

Chronic hepatitis B

Immune‐tolerant phase

Immune‐active phase

Immune‐control phase

Reactivation phase

Immune clearance (cure)

Phases that need anti‐viral drug treatment

Phases that DO NOT need anti‐viral drug treatment

Cirrhosis with any of the phases



Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection




Atypical clinical course of HBV infectionAtypical clinical course of HBV infection HBeAg negative chronic hepatitis

Seroconversion commonly means HBV replication

Mutations in pre‐core or core promotor region

Rapid progression to cirrhosis

HBV reactivation in immuno‐deficient state

De novo hepatitis

Hematopoietic stem cell transplant, rituximab,…

Chronicity rate in new adults’ infection

Difference in geographical distribution and chronicity



HBV Module 4Assessment of liver fibrosis

HBV Module 4Assessment of liver fibrosis



Fibroscan®(http.myliverexam.com/en/lexamen‐fibroscan.html)

AST; aspartate aminotransferase ALT; alanine aminotransferaseAPRI; aspartate aminotransferase‐to‐platelet ratio indexFIB‐4; fibrosis‐4 score

Assessing the degree of liver fibrosisAssessing the degree of liver fibrosis Non‐invasive tests

Components Requirements Cost

APRI AST, platelets Simple serum andhematology test +

FIB‐4 Age, AST, ALT, Platelets

FibroTest gGT, haptoglobin, bilirubin,A1apoprotein, α2‐macroglobulin

Specialized tests atdesigned laboratories ++

Fibroscan ® Transient elastography Dedicated equipment +++

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)



Assessing the degree of liver fibrosis by NITsAssessing the degree of liver fibrosis by NITs

APRI = [ (AST(IU/L)/ AST_ULN(IU/L)) x 100 ] / platelet count (109/L)ULN signifies the upper limit of normal for AST in the laboratory where these investigations were undertaken

FIB‐4 = age(yr) x AST(IU/L)/platelet count(109/L) x [ALT(IU/L)1/2]

Fibrosis stages

assessed

Cut off values for the detection of fibrosis

Cirrhosis(METAVIR F4)

Significant fibrosis(METAVIR ≧F2)

APRI ≧F2, F4 High cut‐off 2.0 High cut‐off 1.5FIB‐4 ≧F3 High cut‐off 3.25

FibroTest ≧F2, F3, F4 0.32‐0.48 0.58‐0.75

Fibroscan® ≧F2, F3, F4 >11‐14 kPa >7‐8.5 kPa




Transient elastography (Fibroscan)Transient elastography (Fibroscan)




Transducer sends a mechanical shearwave

Large explored volume(at least 100 times more than biopsy)

Monitor display of Fibroscan




• Median• Calculated from 10 valid measurement• Is used as the final result

• Inter‐quartile range (IQR)• Spread of the middle half of observations• Should be small

• IQR/median• Ratio of IQR to median• Indicates variability in different reading• High values means large variation• If > 30%, implies no reliability



FibroscanFibroscan

Advantages Easy, non‐invasive Can be done in outpatient or community settings Takes <10 minutes to perform Health‐care staff can be easily trained

Limiting factors High cost of equipment Equipment needs regular maintenance/calibration by trained

personnel No universal cut‐off values for specific stages of fibrosis Difficult to measure in very obese



The Child‐Turcotte‐Pugh Classification systemThe Child‐Turcotte‐Pugh Classification systemPoints 1 2 3

Encephalopathy None Minimal(grade1 or 2)

Advanced(grade 3 or 4)

Ascites Absent Controlled Refractory

Total bilirubin(μmol/L)(mg/dL)

<34 (<2) 34‐51 (2‐3) >51 (>3)

Albumin(g/dL) >3.5 2.8‐3.5 <2.8

Prothrombin time (seconds) or PT‐INR*

<4 or <1.7 4‐6 or 1.7‐2.3 >6 or >2.3

Child‐Pugh Class A: 5‐6 pointsChild‐Pugh Class B: 7‐9 pointsChild‐Pugh Class C: 10‐15 points

*PT‐INR ; prothrombin time international normalized ratio



HBV Module 5Treatment for Chronic Hepatitis B

HBV Module 5Treatment for Chronic Hepatitis B



Other international treatment Guidelines Other international treatment Guidelines

American Association Liver disease 2018

European Association in the Study of Liver disease 2017

Asian Pacific Association for the Study of Liver 2016

Country specific Treatment and Care guidelines



WHO guidelinesWHO guidelinesAssessment for treatment

Monitoring

Stopping treatment



Initial assessment for hepatitis B and CInitial assessment for hepatitis B and C

HBV HCVChronic infection HBsAg Anti‐HCVAcute infection Anti‐HBc IgM HCV RNA, HCcAg etc.

(without anti‐HCV antibody, excluding other hepatitis viruses)

MONITORING AND EVALUATION FOR VIRAL HEPATITIS B AND C: RECOMMENDED INDICATORS AND FRAMEWORK (WHO 2016)



Additional assessment for chronic hepatitisAdditional assessment for chronic hepatitis

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P17‐19

HBV HCVSerological markers

Anti‐HBs/anti‐HBc antibodiesHBe antigen, Anti‐HBe,

HBV DNA

HCV RNA

Severity Aminotransferase (AST/ALT)Bilirubin, albumin, alkaline phosphatase (ALP)

Staging Liver biopsyNon‐invasive tests

‐APRI, FIB‐4, FibroTest, Transietn elastography



Why should we treat HBV infectionWhy should we treat HBV infection Delay the progression of cirrhosis (Improve liver fibrosis)

Reduce the incidence of hepatocellular carcinoma

↓

Improve long‐term survival and QOL

Key outcomes

Sustained ALT normalization

Sustained undetectable HBV DNA

HBeAg seroconversion / HBsAg seroconversion

Reversion of fibrosis stage




Sustained ALT normalization

Sustained undetectable HBV DNA

HBeAg seroconversion

HBsAg seroconversion

HBsAg seroconversion and development of HBsAb = “functional

cure” .. uncommon

Resulting in …

Effects of antiviral therapyEffects of antiviral therapy

1. Lim YS, et al. Gastroenterology. 2014;147:152-161.2. Chang TT, et al. Hepatology. 2010;51:422-430. 3. Zoutendijk R, et al. Gut. 2013;62:760-765. 4. Marcellin P, et al. Lancet. 2013;381:468-475. 5. Papatheodoridis GV, et al. J Hepatol. 2015;62:363-370. 6. Papatheodoridis GV, et al. Hepatol. 2016;63:1481-1492.



Prevention of fibrosis progression

Promoting fibrosis regression, even in cirrhosis

Prevents or even reverses hepatic decompensation

Reduces, but does not eliminate the risk of HCC

Reduce risk of transmission Improve long term survival

and quality of life

Effects of antiviral therapyEffects of antiviral therapy

Fibrosis

Reversal after antiviral



Cure as a Goal of TherapyCure as a Goal of Therapy

Cure not so simple . . . reasons lie in the virology

Actual cureTrue cure = all traces of HBV gone from the liver (like HCV)VERY difficult due to presence of HBV cccDNA

Functional cureUse the markers of pts who do well:1. HBsAg loss (ideally with anti-HBs)2. Possibly sustained off-treatment inactive disease without

HBsAg loss (HBeAg negative, DNA undetectable, normal ALT, normal histology)



Why Is Cure Rare With Nucleos(t)ide Therapy?Why Is Cure Rare With Nucleos(t)ide Therapy?

Grimm D, et al. Hepatol Int. 2011;5:644-653.

O-

5’Cap (A)n 3’

Translocation

dAdAdGnew (-) strand DNA synthesis

pgRNA

DNA synthesis

Encapsidationof pg RNA

HBeAg

Polymeraseprotein

Core protein

Envelope proteins

S, M, L

Golgi complex

ReleaseHBsAg

HBeAg

HBV virion

HBV RNAtranscripts

PregenomicRNA

cccDNADNArepair

Transport to cellnucleus

Attachment andpenetration

Uncoating

Oral anti-HBV therapy



REVEAL: HBV DNA Level andRisk of Cirrhosis

REVEAL: HBV DNA Level andRisk of Cirrhosis

Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

Follow-up (Yrs)

0.4

0.3

0.2

0.1

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Baseline HBV DNA Level (copies/mL)≥ 1 million 100,000-999,99910,000-99,999300-9999< 300

Cum

ulat

ive

Inci

denc

e of

Liv

er C

irrho

sis

Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC in untreated, HBsAg-positive individuals in Taiwan (N = 3582)



REVEAL: HBV DNA Level and Risk of HCCREVEAL: HBV DNA Level and Risk of HCC• Prospective study in same REVEAL cohort (N = 3653)

• Increased HCC incidence with increasing DNA levels (P < .001)• HCC can occur in the absence of cirrhosis

Chen CJ, et al. JAMA. 2006;295:65-73.

Follow-up (Yrs)

Cum

ulat

ive

Inci

denc

e of

HC

C (%

)

6

4

2

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Baseline HBV DNA (copies/mL)≥ 1 million 100,000-999,99910,000-99,999300-9999< 300

12

10

8



Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

HBV Treatment Reduces Risk of Disease Progression Including DecompensationHBV Treatment Reduces Risk of Disease Progression Including Decompensation

*Hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease.

Placebo-controlled, double-blind, parallel group study of pts with chronic HBV infection and cirrhosis (F4) (N = 651) followed until HBeAg seroconversion or disease progression*

P = .001

25

20

15

10

5

030181260 36

n = 198

n = 173

n = 417 n = 385

n = 122

24

Lamivudine

Placebo

MosPts

With

Dis

ease

Pro

gres

sion

(%)



HCC Incidence in Pts with Chronic HBV Infection and Cirrhosis

HCC Incidence in Pts with Chronic HBV Infection and Cirrhosis

1. Wong GL, et al. Hepatology. 2013;5:1537-1547.2. Wu CY, et al. Gastroenterology. 2014;147:143-151.3. Hosaka T, et al. Hepatology. 2013;58:98-107.

2.8

482 69

5.3

3.9

4.9

3016 2847

1.4

7.8

79 85

aHR: 0.72(95% CI: 0.64-0.81)

aHR: 0.55(95% CI: 0.31-0.99) Nucleos(t)ide

analoguesControl

0

2

4

6

8

n =

Hong Kong[1] Taiwan[2] Japan[3]

Ann

ual I

ncid

ence

of H

CC



HBV Treatment Reduces Risk of Liver Transplant

HBV Treatment Reduces Risk of Liver Transplant

Jang JW, et al. Hepatology. 2015;61:1809-1820.

Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707)

Treated,* responder (n = 245)Treated,* nonresponder (n = 178)Untreated (n = 284)

Bonferroni-adjusted P < .0003LT-F

ree

Surv

ival

(%)

Mos0 8412 24 36 48 60 72

100

80

60

40

20

0

*Treated predominantly with lamivudine (n = 203) or entecavir (n = 198).

Antiviral therapy improved transplant-free survival over 5 yrs (P = .0098 vs untreated)



Marcellin P, et al. Lancet. 2013;381:468-475.

Long‐term TDF in Pts With HBV: Regression of Fibrosis, CirrhosisLong‐term TDF in Pts With HBV: Regression of Fibrosis, Cirrhosis

• Overall regression of fibrosis in 51% of pts through 5 yrs (176/348 pts with matched biopsies)

• Reversal of cirrhosis in 74% of pts through 5 yrs (71/96 pts with cirrhosis at baseline)



Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program

Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program

Chiang CJ, et al. Hepatology. 2015;61:1154-1162.

Pts receiving treatment for chronic hepatitis after start of program in 2003 in Taiwan: 157,570 (HBV) and 61,823 (HCV)

Reduced rate of HCC mortality in all age cohorts by 5-8 yrs after introduction of national therapy program

30-39 40-49 50-59 60-69

0.98

0.8

0.6

0.4

0.2

0

Sex-

Adj

uste

d H

CC

M

orta

lity

Rat

e R

atio

0.93*

0.79†

1.00.88*

0.66†

0.92*

0.76† 0.77†

2004-20072008-2011

Age Group (Yrs)*P < .01 vs 2000-2003.†P < .005 vs 2000-2003.



5‐Year Follow‐Up Study: CHB patients on Tenofovir DF

5‐Year Follow‐Up Study: CHB patients on Tenofovir DF

• Multicenter, 3‐year retrospective, 2‐year prospective study (n=357)

• Males (69%)• Mean age: 48 years• Cirrhotics (n=7)• Follow‐up: 65 months

• Cirrhosis progression• No progression among baseline cirrhotics

• New cirrhosis (n=7)• No development of HCC

Ormeci N, et al. Hepatol Int. 2016;10(suppl 1):48. Abstract O-115.

0

20

40

60

80

100

Patie

nts

(%)

88%92%

Normalization

ALT

5-Year Outcomes

83%

AST2%

HBV DNASuppression

NewCirrhosis

Cases

Absence of cirrhosis defined by:Liver biopsy (Metavir F0-F3); or transient elastography (<12.5

kPa); or FibroTest® or FibroSure® (<0.48 with APRI <1).



Long‐term TDF in Pts With HBV: Reversal of Inflammation

Long‐term TDF in Pts With HBV: Reversal of Inflammation

Parameter Outcome at 7 Yrs[1]

Normalized ALT, % (n/N) ITT* On-treatment

57.1 (323/566)80.0 (328/410)

HBV DNA < 29 IU/mL,% (n/N) ITT On-treatment

70.1 (418/596)99.3 (430/433)

HBeAg loss,† % (n/N) 54.5 (84/154)

HBe seroconversion,†% (n/N) 39.6 (61/154)

HBsAg loss,† K-M % (95% CI) 11.8 (8.1, 16.9)

HBs seroconversion,†K-M % (95% CI) 9.7 (6.4, 14.6)

Open-label study of TDF in pts with chronic HBV infection (N = 585)

Necroinflammation improved over 5 yrs(n = 348 matched biopsies)[2]

†HBeAg-positive population. 1. Buti, M et al. Dig Dis ci. 2015;60:1457.2. Marcellin P, et al. Lancet. 2013;381:468-475. 2.

Pts

(%)

P < .001P < .001

80%

Knodell Necroinflammatory Score

8%

100

80

60

40

20

0Baseline Yr 1 Yr 5

10-14 7-9 4-6 0-3



Cho JY, et al. Gut. 2014;63:1943-1950.

Is HBV Suppression the Same as Inactive Disease?

Is HBV Suppression the Same as Inactive Disease?

Complete responders

Inactive CHB

P < .001

Cum

ulat

ive

Inci

denc

e of

HC

C (%

)

Mos

60

50

40

30

20

10

00 12 24 36 48 60 72

Pts at Risk, nNUC CRInactive CHB

11321014

848918

564724

497594

380469

128304

1980

Retrospective cohort study of treatment-naive pts with HBV starting oral nucleos(t)ide analogues (n = 1378) vs HBeAg-negative pts with inactive CHB (n = 1014) Group receiving

nucleos(t)ide analogues divided by continuous viral suppression (complete vsincomplete responder)

Spontaneous control better than treatment



Who Should Be Treated?Who Should Be Treated?

All people with CHB are potential treatment candidates

Not a question of who to treat, but when: treat now or monitor and treat later when indicated

A person who is not a treatment candidate now can be a treatment candidate in the future

→Changes in HBV replica on status and/or ac vity/stage of liver disease

→Availability of new or improved treatments



All Patients with cirrhosis should be treatedAll Patients with cirrhosis should be treated

All patients with cirrhosis should be treated

Life long treatment

Treat with antivirals (Tenofovir or entecavir)

Decompensated cirrhosis based on clinical findings or history

Compensated cirrhosis based on Transient elastography (in clinical context), APRI or FIB 4.

Irrespective of ALT, Hepatitis BeAg status, or HBV viral load



Who should be treatedWho should be treated

• High risk of disease progression to cirrhosis and hepatocellular carcinoma, such as…

Older than 30 years

Persistently abnormal ALT levels

High level HBV replication

• Special populations

Pregnant mothers with high viral load ???

Coinfection with HCV, HIV

Undergoing immunosuppressive therapy



Which patients should we treat for HBVWhich patients should we treat for HBV

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P36‐37

Optimal timing of treatment for HBV is still debated.

HBV HCV• Cirrhosis• High risk of disease progression to

cirrhosis and hepatocellular carcinoma, such as…

Older than 30 years Persistently abnormal ALT levels High level HBV replication

• All patients



Populaiton

HBsAg‐

Non cirrhotic patients aged <30

Normal(<19 F, <30 M)

<2,000

Treatment Deferred

HBsAg+

Non cirrhotic patients aged >30

Fluctuating

2,000‐20,000

Treatment Deferred

Cirrhotic patients or APRI >2

Persistently elevated

>20,000

Treatment Deferred

Treatment Deferred

Treatment Deferred

Treatment Recommended

Treatment Recommended

CIRRHOSIS

No Treatment Required

Summary of WHO Recommendation Summary of WHO Recommendation ALT HBV DNAHBsAg



Who not to treat nowWho not to treat now

Young patients

Persistently normal ALT

No features of advanced fibrosis on APRI or Transient Elastography

No family history of liver disease

If viral load available HBV DNA <2000 and no fibrosis and normal ALT



Phases of CHB infectionPhases of CHB infection

Initiate treatment Initiate treatment



How to treat HBV infectionHow to treat HBV infection Antiviral agents

Interferon (IFN), Pegylated (PEG) ‐IFN

Nucleos(t)ide analogue (NA) ‐ Tenofovir, Entecavir

Lifelong treatment is generally required

Clearance of HBsAg (=Cure) is rare

High rate recurrence in treatment discontinuation

Optimal timing of discontinuation remains unclear

Patient’s motivation is essential




How to Treat HBV‐infected PeopleHow to Treat HBV‐infected People

Antiviral agents: Nucleos(t)ide analogue (NA) ‐ Tenofovir, Entecavir

Long term Rx required, often life long (all patients with

cirrhosis)

Functional cure (loss of HBsAg uncommon 1% per year)

High rates of relapse after stopping Rx

Interferon therapy

Pegylated (PEG) –IFN or standard IFN

Limited role in resource poor setting

Finite duration of Rx 12m, Stopping rules

Role in coinfection with HBV and HDV




Advances in HBV treatmentAdvances in HBV treatment

1957Discoveryinterferon

1991Interferon alfa-2blicensed

1999Lamivudine (3TC)licensed

1991 Discovery lamivudine (3TC)

1990Discovery PMEA

2003Adefovir dipivoxil (PMEA prodrug)licensed

1998 Discoveryentecavir

2006Entecavirlicensed

2007Telbivudinelicensed

2001 Discoverytelbivudine 2005

Peginterferon alfa-2aPeginterferon alfa-2b*

licensed

2008 Tenofovir disoproxil fumaratelicensed

* Specific countries onlyted from: ClinicalCareOptions.com

2017Tenofovir alafenamidelicensed



Antiviral agents for HBVAntiviral agents for HBV

Antiviral agent Potency against HBV Resistance barrier Antivity against

HIV Cost

Interferons Moderate Not applicable Moderate High

Tenofovir High High HighLow (high in HongKong and other Asian countries)

Entecavir High High Weak High

Emtricitabine Moderate Low High Low

Telbivudine High Low Unclear High

Lamivudine Moderate‐high Low High Low

Adefovir Low Moderate None(at 10mg dose) High

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P21



The replication cycle of HBV and sites of action of NAs

The replication cycle of HBV and sites of action of NAs



WHO recommendation: choice of drugWHO recommendation: choice of drug


In all adults, adolescents and children aged 12 years or older in whom antiviral therapy is indicated, the nucleos(t)ide analogues which have a high barrier to drug resistance (tenofovir or entecavir) are recommended.

Entecavir is recommended in children



WHO Recommended First‐line HBV Treatment: Essential Medicines List

WHO Recommended First‐line HBV Treatment: Essential Medicines List

6.4.4.1.1 Nucleoside/Nucleotide reverse transcriptase inhibitors

Remarks

entecavir Oral liquid: 0.05 mg/ mL Tablet: 0.5 mg or 1 mg

- Oral liquid for children (weight-based dose) up to 30 kg. Entecavir approved for children age 2 years.

- Usual dose (adults): 0.5 mg/d oral for compensated liver disease. 1 mg/d for decompensated liver disease (0.5 mg x 2 pills daily)

tenofovirdisoproxilfumarate (TDF)

Tablet: 300 mg (tenofovir disoproxilfumarate – equivalent to 245 mg tenofovir disoproxil)

- Listed in the adult WHO EML for hepatitis B: standard dose.

- NOT listed in the WHO EML for hepatitis B for children and adolescent.

- Approved by US FDA in 2012: 300 mg once daily oral for 12 years of age (35kg) with hepatitis B

EML: essential medicines list

WHO Model List of Essential Medicines 20th List (March 2017) (Amended August 2017): adults, children



Choosing Among Nucleos(t)ide AnaloguesChoosing Among Nucleos(t)ide Analogues

If no comorbidities (for most pts)

When to prioritize ETV over TAF– If less expensive (generic available)– Dosing guidelines for CrCl < 15 mL/min

When to prioritize TAF over ETV– Previous nucleoside exposure[2]

• Lamivudine with or without adefovir resistance

– HIV/HBV coinfection– No dose adjustment for CrCl ≥ 15 mL/min

1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2. EASL. J Hepatol. 2017;67:370-398.

If risk of or preexisting bone or renal disease, prioritize ETV or TAF[2]

Age > 60 yrs Bone disease

Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis

Renal abnormalities eGFR < 60 mL/min/1.73 m2

Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dL) Hemodialysis

Monotherapy with ETV, TDF, or TAF[1,2]



Group Drug and doseChildren 2‐12 years of age and weighing ≥10 Kg

Entecavir once daily as oral solution* (mL) if available

Body weight (Kg) Dose (mL)* once daily10‐11 3>11 to 14 4>14 to 17 5>17 to 20 6>20 to 23 7>23 to 26 8>26 to30

9

>30 10

Entecavir dosing in children Entecavir dosing in children

*Solution containing 0.05 mg/mL (or 0.5 mg in 10 mL)



Tenofovir: adverse effects in the trialsTenofovir: adverse effects in the trials

>10%• Asthenia (11%)• Diarrhoea (16%)• Nausea (11%)• Pain (12%)

1‐10%• Anorexia• Depression• Myalgia• Peripheral neuropathy• Dyspepsia• Rash• Headache• Vomiting• Flatulence• Abdominal pain• Neutropenia• Increased transaminases



Tenofovir Disoproxil Fumarate: Dose in renal impairment

Tenofovir Disoproxil Fumarate: Dose in renal impairment



All pts receiving TDF should undergo periodic monitoring of renal function, including phosphate levels[1]

Chronic HBV Infection: Management of Pts With Renal Impairment

Chronic HBV Infection: Management of Pts With Renal Impairment

1. EASL. J Hepatol. 2017;67:370-398. 2. Entecavir [package insert]. 2017. 3. Tenofovir disoproxil fumarate [package insert]. 2017. 4. Tenofovir alafenamide [package insert]. 2017.

Entecavir[2] TenofovirDisoproxil Fumarate[3]

TenofovirAlafenamide[4]

Reduce dose ifCrCl < 50 mL/min

Reduce dose ifCrCl < 50 mL/min

No dose reduction ifCrCl ≥ 15 mL/min

No dose recommendation atCrCl < 10 mL/min without

dialysis

Not recommended atCrCl < 15 mL/min



Tenofovir Alafenemide (TAF) vs TDF: Mechanism of Action

Tenofovir Alafenemide (TAF) vs TDF: Mechanism of Action

Arribas JR, et al. CROI 2017. Abstract 453. Duarte-Rojo A. Therap Adv Gastroenterol. 2010;3:107-119. Murakami E, et al. Antimicrob Agents Chemother. 2015;59:3563-3569. Tenofovir disoproxil fumarate [package insert]. 2017. Tenofovir alafenamide [package insert]. 2017.

TAF: no dose adjustment needed in pts with CrCl > 15 mL/min

90% lower plasma

TFV than with TDF

GI tract

TDF300 mg

TAF25 mg

Plasma

TFVHepatocyte

Renal tubular

cell

Renal tubular

cell

TFV HBV

TAF: novel prodrug of TDF



TAF vs TDF in Pts with HBV Infection: EfficacyTAF vs TDF in Pts with HBV Infection: Efficacy

1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Chan HL, et al. EASL 2016. Abstract GS12. 3. Buti M, et al. EASL 2016. Abstract GS06.

*ULN for men, ≤ 43 U/L (≤ 35 U/L if age ≥ 69 yrs); for women, ≤ 34 U/L (≤ 32 U/L if age ≥ 69 yrs).†ULN for men, ≤ 30 U/L; for women, ≤ 19 U/L.

HBeAg-Positive Pts[2]

(N = 873)HBeAg-Negative Pts[3]

(N = 425)Outcome, % TAF TDF P Value TAF TDF P ValueHBV DNA < 29 IU/mL at Wk 72[1] 71.6 71.9 .78 92.6 92.1 .84

ALT normalization at Wk 48 Central laboratory criteria* AASLD laboratory criteria†

7245

6736

.18.014

8350

7532

.076<.001

HBeAg Loss at Wk 48 Seroconversion at Wk 48

1410

128

.47

.32

HBsAg Loss at Wk 48 Seroconversion at Wk 48

<1<1

<10

.52

.22

Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis



TAF vs TDF in Pts With HBV Infection: SafetyTAF vs TDF in Pts With HBV Infection: Safety

1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Agarwal K, et al. AASLD 2016. Abstract 1844. 3. Izumi N, et al. AASLD 2016. Abstract 1904.

Outcome TAF TDF P Value

Mean change in BMD at Wk 72, %[1]

Hip Spine

-0.16-0.57

-1.86-2.37

< .001< .001

Median change in serum creatinine at Wk 48, mg/dL[2] 0.01 0.02 .012Median change in eGFR at Wk 48, mL/min[2] -1.2 -5.4 < .001

Mean change in FibroTest score at Wk 48[3]

HBeAg-positive pts HBeAg-negative pts

-0.07-0.05

-0.04-0.03

.007

.028

Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis



Chronic HBV Infection: Management of Pts With NA Resistance

Chronic HBV Infection: Management of Pts With NA Resistance

*Includes either TDF or TAF in EASL guidelines; AASLD guidelines not yet updated since approval of TAF.

1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2. EASL. J Hepatol. 2017;67:370-398.

Resistance Switch Strategy Add StrategyAdefovir Entecavir[1] Entecavir[1]

Entecavir Tenofovir*[1,2] Tenofovir(or emtricitabine/tenofovir*)[1]

Lamivudine Tenofovir*[1,2] Tenofovir(or emtricitabine/tenofovir*)[1]

Telbivudine Tenofovir*[1,2] Tenofovir[1]

Multidrug Tenofovir*[1] Tenofovir* + entecavir[1,2]



Simplified guidelines on selection of patients for Treatment of patients with Chronic hepatitis BSimplified guidelines on selection of patients for Treatment of patients with Chronic hepatitis B



Duration of treatmentDuration of treatment

Cirrhosis or APRI >2.0 Lifelong treatment

Discontinuation may be considered exceptionally in those without cirrhosis (or APRI < 2.0 in adults) and all of the following: Can be followed carefully long‐term for reactivation If HBeAg loss and seroconversion to anti‐HBe, and maintained for

one year Persistently normal ALT Persistently undetectable HBV DNA



Drug doseDrug dose

Adults Entecavir 0.5 mg/day oralTenofovir 300 mg/day oral

Children need dose modification



Drugs need dose adjustment in renal diseaseDrugs need dose adjustment in renal disease



HBV Module 6Monitoring for Chronic Hepatitis B

HBV Module 6Monitoring for Chronic Hepatitis B



Need for monitoringNeed for monitoring

All need monitoring (irrespective of need for treatment)

HBsAg +ve

Defertreatment

Notreatment

Starttreatment



All patients infected with HBV

More frequent monitoring recommended for:

Persons who do not yet meet the criteria for treatment

Persons on treatment or following treatment cessation

Monitoring is essential to confirm

Adherence, toxicities

Treatment effect - ALT, HBsAg, HBeAg, HBV DNA

Hepatocellular carcinoma – Ultrasound and AFP testing


Monitoring patients with CHBMonitoring patients with CHB



Who should we monitor and whyWho should we monitor and why

All patients with chronic HBV and HCV infection

More frequent monitoring is recommended for:

Persons who do not yet meet the criteria for treatment

Persons on treatment or following treatment cessation

Monitoring is essential to confirm

Adherence, toxicities

Treatment effect ‐ ALT, HBsAg, HBeAg, HBV DNA

Hepatocellular carcinoma – Ultrasound and AFP testing




How to monitor?How to monitor?



How to monitor?How to monitor?

At least annually: ALTHBsAg, HBeAg, HBV DNA levelAPRIAdherence to treatmentDrug adverse events (renal function)

More frequent In those who do not clearly meet criteria for treatment Following treatment discontinuation

Surveillance for hepatocellular cancer



How to monitor HBV infected patientsHow to monitor HBV infected patients: every 12 mos

Disease progression/ treatment response

: every 12 monthsMonitoring for

treatment toxicities

: every 6 monthsDetection of liver cancer(cirrhosis / family history)

Adherence Renal function Ultrasound

ALT, HBV DNA, HBeAg Risk factors for renal dysfunction α‐fetoprotein

Non‐invasive test

Baseline 6month 12month 18month 24month…



When to stop treatment of HBVWhen to stop treatment of HBV Possible discontinuation (Persons without cirrhosis)

who can be followed carefully long term for reactivation

HBeAg seroconversion to anti‐HBe and after completion

of at least one additional year of treatment

in association with persistently normal ALT levels

persistently undetectable HBV DNA levels

Retreatment is recommended if there are consistent sign of

reactivation (HBsAg / HBeAg becomes positive, ALT levels

increase, or HBV DNA becomes detectable again)




TIME

HBeAgdecline

HBV DNAsuppression

HBeAg to Anti-HBeseroconversion

Loss ofHBsAg

Anti-HBs+ Cure

Improved histology and survival

= HBsAg seroconversion

Therapeutic endpoints over timeTherapeutic endpoints over time



Why hepatitis B is not curable: A Key Difference Between HCV & HBV

Nuclear cccDNA

Why hepatitis B is not curable: A Key Difference Between HCV & HBV

Nuclear cccDNA



Minimise other hepatic insultsMinimise other hepatic insults

Stop/reduce alcohol intake

Stop/reduce smoking

Stop recreational drug use

Monitor medications

Assess for co‐infections: HIV, HAV (vaccinate), HCV, HDV

Eat a balanced healthy diet

Maintain a healthy body weight

Exercise regularly

Manage stress



HBV Module 7Special population for Chronic Hepatitis B

HBV Module 7Special population for Chronic Hepatitis B



Who are specific populationsWho are specific populations Coinfections

HBV and HCV coinfection

HBV and HDV coinfection

HBV coinfected with HIV

HBV coinfected with Tuberculosis

Pregnant women

Children and adolescents

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P98GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P37, P51



HBV and HCV coinfectionHBV and HCV coinfection 3‐18% of people who are HBsAg(+) are also HCV infected,

and up to 25% of HCV‐infected persons are HBV infected.

Coinfection with HBV/HCV promotes rapid progression of

liver diseases, and increases the risk of HCC.

Indications for treatment of HBV infection in patients

with HBV/HCV coinfection are same as those with HBV

monoinfection.

HBV DNA monitoring may be necessary as there is a

potential risk of HBV reactivation during DAA treatment. GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P103GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P38



HBV and HDV coinfectionHBV and HDV coinfection The routes of HDV transmission are the same as for

HBV but vertical transmission is rare.

5% of HBsAg(+) are coinfected with HDV.

Vaccination against HBV prevents HDV coinfection.

Fulminant hepatitis is more frequently observed in

HBV/HDV coinfection compared to HBV monoinfection.

PEG‐IFN is the only drug effective against HDV;

TDF/ETV are not effective in HBV/HDV coinfection.

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P23, 102



HBV and HIV coinfectionHBV and HIV coinfection HBV/HIV coinfection results in

Higher rates of chronicity after acute HBV infection

Higher levels of HBV replication and rates of

reactivation

Less spontaneous clearance

More rapid progression to cirrhosis

Higher liver‐related mortality

Decreased treatment response

(compared with persons without HIV coinfection)

GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P22



HBV and HIV coinfectionHBV and HIV coinfection 5‐15% of HIV‐infected persons are coinfected with HBV

All HIV infected individuals should be recommended on

ART, regardless of CD4 count.

Patients should be simultaneously treated for HBV/HIV.

Choice of ART should be based on drugs that are active

against both HIV and HBV

Tenofovir (TDF)

Lamivudine (3TC)

Efavirenz (EFV)




HBV and HIV coinfection Several challenges with HBV/HIV coinfection

Cross‐resisitance between HIV and HBV drugs

Increased risk of liver injury

‐ ART‐related immune‐reconstitution can lead to

increased hepatocyte killing

‐ Anti‐HIV drugs can induce direct hepatotoxicity

Severe liver injury may lead to fulminant hepatitis

and death




HBV and tuberculosis (TB) coinfectionHBV and tuberculosis (TB) coinfection


Persons at increased risk of infection with HBV are

also at increased risk of infection with TB.

Drug‐induced liver injury with elevation of

aminotransferase is three‐ to six‐fold higher in

persons coinfected with HBV who are receiving

antituberculosis drugs, due to hepatotoxicity with

isoniazid, rifampicin and pyrazinamide.



HBV infection in pregnant womenHBV infection in pregnant women Mother‐to‐child HBV transmission must be prevented

through a birth dose of hepatitis B vaccine followed by

two or three doses as EMTCT strategies (Module 4)

Indication for treatment in adults with CHB also apply

to pregnant women; however, WHO makes no

recommendation on the routine use of NAs.

Tenofovir may be recommended for pregnant women

based on safety data and resistance profile.

IFN‐based therapy is contraindicated.




Children and adolescents with HBV infectionChildren and adolescents with HBV infection The majority of children with HBV infection will not

require antiviral therapy because

They are usually in the immune‐tolerant phase.

Curative response rates with NAs and IFN are low.

There are concerns over long‐term safety and risks of

drug resistance.

The FDA has approved;

Tenofovir for children with HBV above 12 years.

Entecavir for children with HBV above 2 years.




HBVPractical session

case‐based learning

HBVPractical session

case‐based learning



A 52 year‐old male presents with malaise

History: no previous hospitalization

Social: 120g alcohol/day (30 years), no tobacco, no records of

substance abuse

Examination: unremarkable

Laboratory data:

• AST 78 U/L (ULN 30), ALT 64 U/L

• HBsAg positive, Anti HCV negative

Clinical Question

What test do you order?

Case study 1Case study 1




• HBV DNA 2.8 x108 IU/mL, HIV rapid diagnostic test negative

• Hb 11.8 g/dL, Neutrophil 2.5 x109/L, PLT 98 x109/L

• Alb 3.4 g/dL, T‐Bil 1.2 mg/dL, PT‐INR 1.6

• Cre 1.0 mg/dL

• Ultrasound: chronic liver disease, mild splenomegaly

Clinical Question

What is the stage of liver disease?

Is treatment recommended?

What monitoring do you require?





• APRI 2.6; [78/30]x100/98 > 2.0; Liver cirrhosis (compensated)


• Diagnosis: Liver cirrhosis B

• Select recommended preferred regimen:

Tenofovir 300mg once daily or Entecavir 0.5mg once daily

Lifelong treatment

• Assist for treatment: reduce alcohol intake


• Monitor for efficacy and toxicity (baseline and every 12 months)

• Long life screening for HCC (every 6 months)




A 28 year‐old female presents for a health check up

Complaints: not any symptoms


Social: no records of alcohol, tobacco and substance


Laboratory data:

• She has found to be 24 weeks of gestation

• HBsAg positive, Anti HCV negative, HIV RDT negative

Clinical Question






• HBV DNA 1.7 x108 IU/mL


• AST 58 U/L (ULN 30), ALT 62 U/L


• Cre 0.8 mg/dL, normal urine

• Ultrasound: normal liver, no ascites, no hepatoma

Clinical Question







• APRI 1.0; [58/30]x100/188 < 2.0; not liver cirrhosis


• Diagnosis: chronic hepatitis B, 24 weeks of gestation

• Infant and neonatal hepatitis B vaccination:

All infants should receive their first dose of hepatitis B vaccine

as soon as possible after birth, preferably 24 hours, followed by

two or three doses.

• Prevention of mother‐to‐child HBV transmission

no recommendation

• Breast feeding is safe.




A 45 year‐old female presents with insomnia


Social: no records of alcohol, tobacco and substance


Laboratory data:

• Hb 12.6 g/dL, AST 34 U/L (ULN 30), ALT 40 U/L

• HBsAg positive, Anti HCV negative

Clinical Question







• Neutrophil 3.0 x109/L, PLT 218 x109/L


• Cre 0.8 mg/dL


Clinical Question










• Diagnosis: Chronic hepatitis B



Lifelong treatment


• Monitor for efficacy and toxicity (baseline and every 12 month)




A 26 year‐old male presents with low grade fever


Social: 60g alcohol/day (6 years), there are records of substance

abuse, Sexually active with several partners

Examination: injection scar of arm

Laboratory data:


• AST 112 U/L (ULN 30), ALT 120 U/L, HBsAg positive

Clinical Question








• Cre 0.8 mg/dL

• Anti‐HCV negative, HIV RDT negative


Clinical Question










• Diagnosis: chronic hepatitis B



Lifelong treatment

• Assist for treatment: alcohol sobriety, drug abstinence


• Monitor for efficacy and toxicity (baseline and every 12 month)





52‐year‐old man

Planned for laparoscopic cholecystectomy

Detected to have HBsAg positive on evaluation

• History• No previous hospitalization• No addiction

• Examination: unremarkable

What tests should one order?



Investigations ValuesHemoglobin (g/dL) 11.8Platelets (x 109/L) 98Total bilirubin (mg/dL) 1.2Albumin (g/dL) 3.4ALT (IU/L)AST (IU/L)

66 (<40 IU/L)98 (<40 IU/L)

Prothrombin time (INR) 1.6HBV DNA (IU/L) 1,120USG abdomen Coarse echo‐texture of liver

Portal vein diameter = 14 mmSplenomegaly, no ascites

Case study 5: Test resultsCase study 5: Test results



Case study 5: Issues in managementCase study 5: Issues in management


Cirrhosis versus no cirrhosis

Compensated versus decompensated


What drug?

How long?

How would you monitor the person during treatment?



Case study 5: QuestionsCase study 5: Questions



What is the treatment?

What is the monitoring required?




What is the stage of liver disease?– APRI = [98/40] x 100/98 = ~2.5– APRI > 2.0 Liver cirrhosis (compensated)








Is treatment recommended?– HBV DNA is detectable: Those with cirrhosis need treatment

(irrespective of DNA level)









What is the treatment?– Entecavir 0.5 mg, once daily, oral, life-long





What is the stage of liver disease?– APRI = [98/40] x 100/98 = ~2.5 – APRI > 2.0 Liver cirrhosis (compensated)



What is the treatment?– Entecavir 0.5 mg, once daily, oral, life-long

What is the monitoring required?– Monitor for efficacy, decompensation and liver cancer Lifelong



Case study 5: Take home messagesCase study 5: Take home messages

Cirrhosis must be looked for in all HBsAg positive patients

In patients with cirrhosis and detectable HBV DNA Antiviral drugs should be started (regardless of HBV DNA level) Serum ALT level has no role in deciding the need for treatment

In patients with cirrhosis, antiviral treatment Should be continued for life Entecavir is preferred over tenofovir (the latter has renal toxicity) Usual dose of entecavir is 0.5 mg/d even in compensated cirrhosis,

but is 1.0 mg/d in decompensated cirrhosis




25 y old woman Detected HBsAg positive during blood donation screening• Asymptomatic, good health• No previous hospitalization, no morbidity, no addiction• Examination: unremarkable

• What test should one order?




34 (<40 IU/L)28 (<40 IU/L)

Prothrombin time (INR) 1.1HBV DNA (copies/ml) 8000USG abdomen Normal liver size and echotexture

Portal vein diameter = 10 mmNormal spleen; no ascites






–







What is the stage of liver disease?– APRI = [28/30] x 100/218 = ~0.4– APRI < 2.0 No cirrhosis








Is treatment recommended?– ALT normal– HBV DNA = 8000 copies/ml = ~ 8000/5 or 1600 IU/mL








What is the treatment?– No treatment (immune control phase)







What is the treatment?– No treatment (immune control phase)

What is the monitoring required?– Monitor for disease activity and liver cancer



Case study 6: Take home messagesCase study 6: Take home messages

In young patients without cirrhosis: No need for treatment, unless ALT as well as HBV DNA are high However, all patients need periodic monitoring or disease activity

and for HCC

HBV DNA levels should be expressed as IU/mL (if reported as copies/ml, convert before interpretation)




38 y old woman Incidentally detected HBsAg positive during treatment for

primary infertility• No previous hospitalization, other disease or addiction• Examination: normal

What tests should one order?




76 (<40 IU/L)56 (<40 IU/L)

Prothrombin time (INR) 1.2HBV DNA (IU/ml) 123,000USG abdomen Normal liver size and echotexture

Portal vein diameter = 10 mmNormal spleen; no ascites




Investigations ValuesHemoglobin 10.8 g/dLPlatelets 255 x 109/L

Total bilirubin 1.2 mg/dLAlbumin 3.8 g/dLALTAST

76 IU/L (<30 IU/L)56

Prothrombin time INR 1.2HBV DNA quantitative 123,000 IU/mLUSG abdomen • Normal size liver

• Portal vein diameter 10 mm• No splenomegaly or ascites

What test would you order?






–








Is treatment recommended?– ALT high – HBV DNA = 123,000 IU/mL (>20,000 IU/mL)








What is the treatment?– Tenofovir, 300 mg, once daily, oral







What is the treatment?– Tenofovir, 300 mg, once daily, oral

What is the monitoring required?– Monitor for response, drug toxicity and liver cancer



Take home messages: Case study 7Take home messages: Case study 7

Patients with HBV infection, who have high ALT and high HBV DNA need treatment with antiviral drugs

In absence of cirrhosis, either tenofovir or entecavir may be used, tenofovir is the preferred drug

Such patients need periodic monitoring for drug response, toxicity and HCC

advanced modules for hbv · hepatitis b vaccine contains a viral protein: ‘hbsag= hepatitis b...

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